Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica.
Metronidazole resistance has been induced in an axenic strain of Entamoeba histolytica (HTH-56:MUTM) following continuous exposure to steadily increasing drug concentrations. The drug-resistant line is routinely maintained in normally lethal levels of metronidazole (10 microM). Resistance to this concentration of drug was developed over 177 days. Decreased pyruvate:ferredoxin oxidoreductase (PFOR) activity in anaerobic organisms is one mechanism of metronidazole resistance but in entamoeba, PFOR activity was not decreased in metronidazole-resistant parasites as determined by immunofluorescent assays and immunoblotting studies. 2-Oxoacid oxidoreductase activity, which appeared to be due to a single enzyme, PFOR, was evident with pyruvate as well as the alternative substrates, alpha-ketobutyrate, alpha-ketoglutarate and oxaloacetate. A marked increase in superoxide dismutase (SOD) activity was detected in metronidazole-resistant E. histolytica. Increased SOD activity has not previously been documented as a mechanism of drug resistance although SOD has been associated with a range of stress situations in other organisms.
Samarawickrema
N A
NA
Queensland Institute of Medical Research, The Bancroft Centre, Brisbane, Australia.
Brown
D M
DM
Upcroft
J A
JA
Thammapalerd
N
N
Upcroft
P
P
D000818:Animals; D004351:Drug Resistance; D004748:Entamoeba histolytica / Q000187:drug effects* / Q000201:enzymology*; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D008795:Metronidazole / Q000494:pharmacology*; D050743:Pyruvate Synthase; D013482:Superoxide Dismutase / Q000378:metabolism*
D008795:Metronidazole; D013482:Superoxide Dismutase; D007658:Ketone Oxidoreductases; D050743:Pyruvate Synthase